Tissue transglutaminase (TGase) is a unique enzyme that contains both an enzymatic transamidation activity that crosslinks proteins to other proteins or polyamines and a GTP-binding capability similar to other classical GTP-binding proteins. Although there is limited information as to the signal transducing effects of GTP-bound TGase, the transamidation process of the TGase has been well studied. The transamidation function of TGase serves to posttranslationally modify proteins by cross-linking them to other proteins or polyamines through a reaction in which donor glutamine residues are covalently linked to acceptor primary amino groups. The generation of these new protein- protein or protein-polyamine complexes by TGase has been implicated in modulating normal cellular processes including: maintenance of the extracellular matrix network, cell differentiation, and apoptosis. On the other hand, aberrant TGase activity has also been linked to the progression of human cancers, cataracts, and neurodegenerative disorders. We and others have shown that retinoic acid (RA)- induced cell differentiation was tightly coupled to increases in both the GTP- binding and transamidation activities of the TGase. This, combined with the observations that the TGase is frequently up-regulated by environmental stresses, suggests that TGase may function to ensure cell survival under conditions of differentiation or cell stress. To investigate this possibility, we will determine: (1) the involvement of TGase in protecting cells from apoptosis and assess whether the GTP-binding and/or transamidation activity of the TGase is essential for this biological response to occur, (2) gain insight as to how TGase activity is regulated in cells by purifying a putative TGase regulatory factor, and (3) determine how differentiation factors other than RA mediate TGase activation.